ICCE Institute, Washington University School of Medicine, St. Louis, MO 63110, United States; Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States.
Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States.
Nucl Med Biol. 2018 Apr;59:29-35. doi: 10.1016/j.nucmedbio.2017.11.008. Epub 2017 Dec 1.
Ga[Ga]-Galmydar is an avid transport substrate of ABCB1 (P-Glycoprotein; 170kDa plasma membrane protein), breast cancer resistance protein (BCRP; ABCG2; 72kDa), penetrates human epidermal carcinoma (KB3-1), breast cancer (MCF7), embryonic kidney (HEK 293) tumor cells and rat cardiomyoblasts, and localizes within the mitochondria of tumor and myocardium cells. Ga[Ga]-Galmydar excretes from blood pool quickly, and shows stable retention within rat myocardium in vivo for extended periods, therefore, the agent shows potential to enable myocardial perfusion imaging. The PET tracer also demonstrates ability to probe viability of the blood brain barrier (BBB) in WT mice compared with their mdr1a/1b (dKO) and mdr1a/1b/ABCG2 (t-KO) counterparts. Herein, we report dosimetry data for Ga[Ga]-Galmydar in mice, and extrapolate that information to determine effective dose (ED) for human studies.
To further assess safety profiles of Ga[Ga]-Galmydar for enabling its deployment as a PET imaging probe for biomedical imaging in vivo, we estimated human radiation dosimetry extrapolated from mice biodistribution data. To accomplish this objective, Ga[Ga]-Galmydar was injected intravenously into tails, mice were euthanized, organs harvested (5min, 15min, 30min, 60min, 120min), counted, radiation doses to each organ, and whole body were also determined.
The effective dose (ED) have been found to be 0.021mGy/MBq in males and 0.023mGy/MBq in females. The highest radiation dose was estimated to the kidneys with a value of 0.17mGy/MBq for males and 0.19mGy/MBq for females with contribution from activity in the urine prior to excretion. The critical organ in humans has been determined to be the gall bladder. These data provide preliminary projections on human dosimetry derived from rodent estimates thus providing platform for further validation of dosimetry analysis in human subjects.
Combined data obtained from radiation dosimetry studies in mice indicate that Ga[Ga]-Galmydar would be safe for further evaluation of dosimetry toxicity and myocardial perfusion PET imaging in humans.
Ga[Ga]-Galmydar 是 ABCB1（P-糖蛋白；170kDa 质膜蛋白）、乳腺癌耐药蛋白（BCRP；ABCG2；72kDa）的活性转运底物，可穿透人表皮癌（KB3-1）、乳腺癌（MCF7）、胚胎肾（HEK 293）肿瘤细胞和大鼠心肌细胞，并定位于肿瘤和心肌细胞的线粒体中。Ga[Ga]-Galmydar 从血池快速排泄，并在体内大鼠心肌中表现出稳定的长时间保留，因此该药物具有实现心肌灌注成像的潜力。该 PET 示踪剂还能够探测 WT 小鼠血脑屏障（BBB）的存活能力，与 mdr1a/1b（dKO）和 mdr1a/1b/ABCG2（t-KO）的小鼠相比。在此，我们报告了 Ga[Ga]-Galmydar 在小鼠中的剂量学数据，并推断出该信息以确定人体研究的有效剂量（ED）。
为了进一步评估 Ga[Ga]-Galmydar 用于使 PET 成像探针在体内生物医学成像中的安全性，我们根据小鼠生物分布数据估计了人体辐射剂量学。为了实现这一目标，将 Ga[Ga]-Galmydar 静脉内注射到尾巴中，然后处死小鼠，采集器官（5min、15min、30min、60min、120min），计数，还确定了每个器官和全身的辐射剂量。
已发现雄性的有效剂量（ED）为 0.021mGy/MBq，雌性的 ED 为 0.023mGy/MBq。估计男性的最高辐射剂量是肾脏，为 0.17mGy/MBq，女性的最高辐射剂量为 0.19mGy/MBq，这是由于尿液排泄前的活性所致。在人类中，关键器官是胆囊。这些数据提供了基于啮齿动物估计值的人体剂量学初步预测，从而为人体受试者的剂量学分析进一步验证提供了平台。
从小鼠辐射剂量研究中获得的综合数据表明，Ga[Ga]-Galmydar 可安全用于进一步评估人类的毒性和心肌灌注 PET 成像的剂量学。
